CD36 is a multifunctional receptor that is expressed in various types of cells and tissues including brain microglia and astrocytes as well as monocytes/macrophages and adipocytes. CD36 recognizes many ligands including oxidized or modified low density lipoprotein (oxLDL, mLDL), long-chain fatty acids (LCFA), lipid and lipoprotein components of bacterial cell walls, thrombospondin (TSP) -1 and -2, fibrillar β-amyloid (fAβ), and dying cells (for detailed review see Febbraio, M., et al., J Clin Invest 108:785-791 (2001); Febbraio, M., et al., Int J Biochem Cell Biol 39:2012-2030 (2007)). Ligand recognition by CD36 initiates a signaling cascade that, on phagocytic cells such as macrophages, leads to phagocytosis of the ligand (such as lipids and fatty acids) and any other material the ligand may be bound to, such as cellular components, bacteria, etc. Internalization of oxLDL by CD36-expressing macrophages can lead to the formation of lipid-rich “foam cells” and atherosclerotic plaque, proinflammatory reactions, cytokine release, and/or production of reactive oxygen species, while internalization of β-amyloid peptide by CD36-expressing microglial cells may contribute to Alzheimer's disease (Silverstein R L et al, Sci Signal 2:re3 (2010)). CD36 is also expressed on taste bud cells and gut cells, and has been shown to be involved in preference for high-fat foods (Laugerette F et al., J Clin Invest 115:3177-3184 (2005)).
As consequence of its broad expression and ability to recognize many ligands, CD36 participates in the regulation of many processes including inflammation, angiogenesis, native immunity, clearance of foreign and native substances from the body, and lipid metabolism. Increased CD36 expression/function is associated with the pathology of atherosclerosis, stroke, and neurodegenerative diseases (Febbraio, M., et al., J Clin Invest 108:785-791(2001)).
Although its role in atherosclerotic lesion development is known, CD36's effects on body weight and insulin sensitivity are not clear. This lack of clarity results in part from the different genetic models used for study of metabolism and is compounded by multiple methods of removing or reducing CD36 in these models. A common atherosclerosis and lipid disease model organism is the Apolipoprotein E knockout (“ApoE KO”) mouse, which lacks the ability to clear very low density lipoprotein particles from the body (Zhang et al., Science 258: 468-471, 1992). ApoE KO mice fed a normal diet develop hypercholesterolemia and atherosclerotic plaques, although they do not develop obesity in the absence of a high fat diet. ApoE/CD36 double knockout mice fed a high-fat diet exhibited a slightly increased body weight compared to ApoE KO mice fed a high fat diet in one study (Febbraio, M., et al., J Clin Invest 105:1049-1056 (2000)); however, another study found no difference in body weight between ApoE KO mice and ApoE KO mice treated with the CD36 antagonist EP80317 (Marleau, S., et al., Faseb J 19:1869-1871 (2005)).
Some evidence indicates that CD36 expression and/or function may be linked to diabetic conditions. However, CD36's role in insulin resistance is quite controversial. There is a potential interplay between impaired insulin sensitivity and the modulation of CD36 mediated inflammatory responses. In diabetic ob/ob mice, expression of macrophage CD36 increases in response to impaired insulin signaling, and administration of rosiglitazone (an insulin sensitizer) reduces CD36 expression in these mice (Liang C P, et al., J Clin Invest 113:764-773 (2004)). In addition, an association between glucose and CD36 expression has been identified (Sampson, M. J., et al., Atherosclerosis 167:129-134 (2003); Greenwalt, D. E., et al., J Clin Invest 9:1382-1388 (1995); Susztak, K., et al., PLoS Med 2, e45 (2005)). These findings indicate that CD36 is involved in impairment of insulin signaling. On the other hand, SHR rats that express a mutant CD36 are diabetic (Aitman, T. J., et al., Nat Genet 21:76-83 (1999)). CD36 KO mice that exhibit more proatherogenic profiles are not diabetic (Febbraio, M., et al., J Biol Chem 274:19055-19062 (1999)). These findings suggest a significant underlying complexity of CD36 in the regulation of carbohydrate/lipid metabolism, in which further research is needed.